Uptravi Drug Interactions

In vitro studies: Selexipag is hydrolysed to its active metabolite by carboxylesterases [see Pharmacology: PHARMACOKINETICS under Actions]. Selexipag and its active metabolite both undergo oxidative metabolism mainly by CYP2C8 and to a smaller extent CYP3A4. The glucuronidation of the active metabolite is catalysed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a substrate of P-gp, and the active metabolite is a substrate of the transporter breast cancer resistance protein (BCRP).
Selexipag and its active metabolite do not inhibit or induce cytochrome P450 enzymes or transport proteins at clinically relevant concentrations.
In vivo studies: PAH-specific therapies: In the Phase 3 placebo-controlled study in patients with PAH, no relevant changes in the exposure (area under the plasma concentration-time curve during a dose interval) to selexipag and its active metabolite were observed when administered in combination with an ERA and/or PDE-5 inhibitor. Patients on combination PAH therapy experienced a greater number of adverse events including anaemia in some patients.
Anticoagulants or inhibitors of platelet aggregation: Selexipag is an inhibitor of platelet aggregation in vitro. In the Phase 3 placebo-controlled study in patients with PAH, no increased risk of bleeding was detected with selexipag compared to placebo, including when selexipag was administered with anticoagulants (such as heparin, coumarin-type anticoagulants) or inhibitors of platelet aggregation. In a study in healthy subjects, selexipag (400 micrograms twice a day) did not alter the exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 20 mg warfarin. Selexipag did not influence the pharmacodynamic effect of warfarin on the international normalised ratio. The pharmacokinetics of selexipag and its active metabolite were not affected by warfarin.
Lopinavir/ritonavir: In the presence of 400/100 mg lopinavir/ritonavir, twice a day, a strong CYP3A4, OATP (OATP1B1 and OATP1B3), and P-gp inhibitor, exposure to selexipag increased approximately 2-fold, whereas the exposure to the active metabolite of selexipag did not change.
Rifampicin: In the presence of 600 mg rifampicin, once a day, an inducer of CYP2C8 and UGT enzymes, the exposure to selexipag did not change whereas exposure to the active metabolite was reduced by half. Dose adjustment of UPTRAVI may be required with concomitant administration of inducers of CYP2C8 (e.g., rifampicin).
Midazolam: At steady state after up-titration to 1600 μg selexipag twice a day, no change in exposure to midazolam, a sensitive intestinal and hepatic CYP3A4 substrate, or its metabolite, 1-hydroxymidazolam, was observed. Concomitant administration of selexipag with CYP3A4 substrates does not require dose adjustment.
Inhibitors of UGT1A3, and UGT2B7: The effect of strong inhibitors of UGT1A3 and UGT2B7 (such as valproic acid), on the exposure to selexipag or its active metabolite has not been studied. Caution is recommended when administering these drugs concomitantly with selexipag. Concomitant administration may result in a significant exposure to selexipag or its active metabolite.
Inhibitors of CYP2C8: In the presence of 600 mg gemfibrozil, twice a day, a strong inhibitor of CYP2C8, exposure to selexipag increased approximately 2-fold whereas exposure to the active metabolite increased approximately 11-fold. Concomitant administration of UPTRAVI with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated (see CONTRAINDICATIONS).
Concomitant administration of selexipag with clopidogrel (loading dose 300 mg or maintenance dose of 75 mg once a day), a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag but increased the exposure to the active metabolite by approximately 2.2-fold and 2.7-fold following loading dose and maintenance dose, respectively. Dosing frequency of UPTRAVI should be reduced to once daily when co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel, deferasirox, teriflunomide). Dosing frequency of UPTRAVI should be reverted to twice daily when co-administration of moderate CYP2C8 inhibitor is stopped (see Dosage adjustment with co-administration of moderate CYP2C8 inhibitors under DOSAGE & ADMINISTRATION).
Hormonal contraceptives: specific drug-drug interaction studies with hormonal contraceptives have not been conducted. Although multiple-dose treatment with selexipag did not affect the exposure to the CYP3A4 substrates midazolam and r-warfarin or the CYP2C9 substrate s-warfarin and no reduced efficacy of hormonal contraceptives is expected, caution should be exercised (see USE IN PREGNANCY & LACTATION).
Pharmacodynamic interactions: Reductions in blood pressure may occur when UPTRAVI is administered with diuretics, antihypertensive agents, or other vasodilators.